Water-Soluble Vitamins: Folate, Vitamin B12, and Vitamin C
Introduction to Water-Soluble Vitamins and Homocysteine
This lecture covers three water-soluble vitamins: folate, vitamin B12, and vitamin C, discussing their physiological roles, recommended intake, food sources, risk factors for deficiency and toxicity, and signs/symptoms of deficiency and toxicity.
Homocysteine Definition:
An amino acid not supplied by the diet.
Can be converted into cysteine or recycled into methionine (an essential amino acid) with the aid of specific B vitamins.
Elevated levels of homocysteine are associated with increased cardiovascular, cerebrovascular, and thromboembolic diseases.
Thromboembolic diseases: Conditions caused by a blood clot forming, breaking off, and obstructing blood flow in an artery or vein.
B vitamin involvement in homocysteine metabolism is an area of recent nutrition research.
Folate
Primary Co-enzyme Form: Tetrahydrofolate (THF).
Physiological Roles:
Part of an enzyme that transfers one-carbon compounds arising during metabolism.
Involved in various reactions, including:
Conversion of vitamin B12 into one of its co-enzyme forms.
Synthesizing DNA (adequate DNA synthesis is required for normal cell division).
Deriving methionine from homocysteine.
Role in Fetal Neural Tube Development:
During fetal development, the brain and spinal cord develop from the neural tube.
Defects in neural tube formation during the first few weeks of pregnancy can result in central nervous system disorders (e.g., spina bifida) or even death.
Folate supplementation has been associated with decreased neural tube defect incidence.
Epidemiological Challenge: Women often do not know they are pregnant until the fifth week, after the neural tube has already formed. This raises the question of how to ensure women of childbearing age have adequate folate status at baseline prior to conception.
Mass Fortification of Grains:
The connection between folate deficiency and neural tube defect incidence led to mass fortification of grains with folate in the U.S.
After fortification began, the prevalence of neural tube defects decreased, which is a positive change for pregnant individuals, as pregnancy is a heavily folate-dependent process.
Debate and Risks: However, individuals who never become pregnant may be at risk for excessive folate intake. An estimated 5\% of the U.S. population currently exceeds the Upper Intake Level (UL) for folate.
The risks and benefits of folate fortification are currently being debated.
Folate Forms:
Food Folate: Naturally occurring (e.g., spinach, asparagus, various fruits and vegetables).
Folic Acid: Synthetic form, added to fortified grains (e.g., breakfast cereal, spaghetti noodles).
Folic acid is 1.7 times more bioavailable (available for use by the body) than the food form, which increases the toxicity risk, especially among individuals who never become pregnant.
Measurement: Folate is measured in Dietary Folate Equivalents (DFE) to encompass both forms.
Recommended Dietary Allowance (RDA) (National Institutes of Health):
Adults: 400 micrograms of DFE per day.
During pregnancy: Increases to 600 micrograms per day.
Reminder: 1,000 micrograms = 1 milligram.
Folate Deficiency:
Because folate is integral to DNA synthesis and thus cell division, cell division is impaired in the setting of deficiency.
Macrocytic Anemia: When folate deficiency disrupts red blood cell division, it results in the production of fewer, larger red blood cells.
Additional deficiency symptoms include impaired mucous membrane and skin integrity, and elevated blood concentrations of homocysteine.
Interrelation with Vitamin B12:
The activity of folate is dependent on adequate vitamin B12 status; these two water-soluble vitamins are highly interrelated.
Some deficiency symptoms of folate and B12 overlap, which can allow high folate intake levels to mask vitamin B12 deficiency, making B12 deficiency challenging to diagnose and treat.
Tolerable Upper Intake Level (UL):
To prevent the masking of vitamin B12 deficiency, a UL for folate at 1 milligram (or 1,000 micrograms) per day for adults has been developed.
The UL refers to the synthetic form of folate (folic acid), as reaching toxicity from the food form of folate alone is highly unlikely.
Vitamin B12 (Cobalamin)
Key Concepts about the Nervous System:
Neuron (Nerve Cell): The basic unit of the nervous system (human brain contains about 100 billion neurons).
Anatomy: A neuron has a cell body (including the nucleus) and special extensions called axons and dendrites.
Nerves: Bundles of axons found throughout the body, allowing neurons to communicate across long distances.
Myelin Sheath: A covering along the axon that insulates it and promotes strong, efficient nerve signal transmission.
Physiological Roles:
Acts as a co-factor for two enzymes that maintain the health and integrity of the myelin sheath, thus supporting nerve signal transmission within the body. This role is specific to B12.
Involved in the regeneration of the amino acid methionine from homocysteine (shared with folate).
Involved in the synthesis of DNA and RNA (shared with folate). As a reminder, DNA synthesis is required for cell division.
B12 and folate also depend on each other for activation.
Summary: B12's role in cell division overlaps with folate, but its role in supporting strong nerve signal transmission is specific to B12.
Absorption (Complex Process):
Vitamin B12 is typically found in high-protein foods.
Step 1: Hydrochloric acid (HCl)-induced protein denaturation and pepsin-induced protein digestion in the stomach release B12 from its surrounding proteins.
Step 2: A compound called intrinsic factor, secreted from gastric cells, binds to vitamin B12.
Step 3: The B12-intrinsic factor complex travels through the pyloric sphincter to the small intestine, where it is absorbed into the bloodstream.
Critical Point: Vitamin B12 cannot be recognized by receptors in the small intestine if it is not attached to intrinsic factor.
Recommended Dietary Allowance (RDA): Exists for most stages of the life cycle, measured in micrograms.
Food Sources:
Found almost exclusively in animal-derived foods such as meat, eggs, and dairy products.
Not found in plant-derived foods naturally.
For those following plant-based or vegan diets, nutritional yeast fortified with vitamin B12 can be a good supplementation option.
Risk Factors for Deficiency:
Many cases are due to inadequate absorption rather than inadequate intake, owing to the complex absorption process.
Insufficient Hydrochloric Acid or Intrinsic Factor: If the stomach produces insufficient HCl or intrinsic factor, B12 absorption is hindered.
Atrophic Gastritis: A condition where stomach cells atrophy, leading to reduced HCl and intrinsic factor production. Worldwide prevalence is estimated at 25\% and risk increases with age. In such cases, oral supplementation is ineffective.
Stomach Tissue Removal: Surgical removal of stomach tissue (e.g., for gastric bypass surgery, cancer, or ulcers) also diminishes the secretory capacity of stomach cells.
Clinical Solution for Absorption Issues: In situations of impaired absorption, B12 must be given via injection or nasal spray to prevent deficiency, a common practice in clinical settings.
Inadequate Consumption: Possible for individuals following a vegan diet due to B12's absence in plant-derived foods. Oral vitamin B12 supplements or nutritional yeast are often recommended.
Signs and Symptoms of Deficiency:
Macrocytic Anemia: Impaired DNA synthesis negatively impacts red blood cell division, resulting in the production of larger, fewer red blood cells (similar to folate deficiency).
Peripheral Neuropathy: Due to B12's role in maintaining the health and integrity of the myelin sheath surrounding nerve fibers.
Hallmark Sign: Decreased vibratory sense in the feet, which can be assessed clinically by testing if an individual can sense the vibration of a tuning fork on their big toe.
Tolerable Upper Intake Level (UL):
No UL has been set for vitamin B12 because insufficient scientific literature is available regarding the health effects of excessive intake.
Vitamin C (Ascorbic Acid)
Physiological Roles (Divided into two main categories):
1. Co-factor:
Facilitates the synthesis of certain neurotransmitters and hormones (e.g., serotonin, norepinephrine, thyroid hormone), thereby supporting increases in metabolic rate and cognitive demand.
Participates in protein metabolism.
Collagen Synthesis: Collagen is an essential part of connective tissue, responsible for much of the body's non-skeletal structural integrity. It is heavily involved in wound healing and promotes blood vessel integrity.
2. Antioxidant:
Antioxidant Definition: A substance that protects cells from the damage caused by free radicals.
Free Radicals: Unstable molecules made by the process of oxidation during normal metabolism. They may play a part in cancer, heart disease, stroke, and other diseases of aging.
Vitamin C protects the body from free radicals, decreasing systemic oxidative stress.
Recommended Dietary Allowance (RDA) (National Institutes of Health):
Adults: Ranges from 75 to 90 milligrams per day.
For individuals who smoke regularly: The RDA increases by 35 milligrams per day due to the physiological stress caused by smoking and the relevant roles of vitamin C.
Food Sources:
Exists in a wide variety of fresh fruits and vegetables.
Commonly associated with citrus fruits (oranges, grapefruit, lemons, limes).
Example: A red bell pepper contains more vitamin C than an orange.
Deficiency (Scurvy):
Relatively rare in the United States.
The timeline for development varies based on body stores, but signs can appear within one month of little to no vitamin C intake (considered less than 10 milligrams per day).
Scurvy Symptoms (various and severe): Bleeding gums, pinpoint hemorrhages (capillaries breaking under the skin spontaneously), delayed collagen synthesis, degeneration of muscle tissue, rough/scaly/dry skin, poor wound healing, bone malformation (among the pediatric population), loosening of the teeth, anemia, neurologic symptoms (e.g., hysteria, depression).
If left untreated, massive internal bleeding can be fatal.
Toxicity (with Supplementation):
Vitamin C is a commonly supplemented micronutrient, and a tolerable upper intake level (UL) has been established due to negative health outcomes observed with high-dose supplementation.
Toxicity Symptoms: Nausea, abdominal cramps, headache, fatigue, insomnia, hot flashes, rashes, and diarrhea.
Kidney Stones: Vitamin C supplementation may increase the risk of developing kidney stones; this is an ongoing area of nutrition research.
Clinical Implication: High-dose vitamin C supplementation leads to its presence in the urine, which can skew diagnostic urinalysis tests (e.g., for glucose, ketone, hemoglobin, electrolytes). It is beneficial to ask patients about vitamin C supplement use when conducting a urinalysis.
Conclusion
Folate, vitamin B12, and vitamin C are water-soluble vitamins.
Folate and Vitamin B12: Both are heavily involved in cell division; deficiency in either causes macrocytic anemia. Non-pregnant individuals may obtain excessive folate due to widespread grain fortification.
Vitamin B12: Heavily involved in promoting strong, efficient nerve signal transmission; deficiency results in peripheral neuropathy.
Vitamin C: Heavily involved in promoting the non-skeletal structural integrity of the body; toxicity is possible with supplementation and leads to negative health outcomes.